Pompe disease is a metabolic disease of the muscle. It is also classified as a lysosomal
storage disease (LSD) or a glycogen storage disease. It is an autosomal recessive genetic disorder caused by a deficiency or dysfunction
of acid alpha-glucosidase (GAA), a lysosomal enzyme responsible for the degradation of glycogen. This enzymatic defect results in lysosomal
glycogen accumulation in multiple tissues, with cardiac and skeletal muscle tissues most seriously affected.
In the fatal infantile-onset form, the disease presents rapidly with hypotonia, generalized muscle weakness,
and hypertrophic cardiomyopathy. Death usually occurs within one year of birth due to cardio-respiratory failure.
The late-onset form of Pompe disease, which was discovered more than 30 years after the
infantile-onset form, is more clinically heterogeneous, with greater variation in age of symptom onset, clinical presentation,
and disease progression. Late-onset patients may have residual GAA activity less than 40% of normal when measured in skin
fibroblasts. Generally characterized by slowly progressive proximal muscle weakness and respiratory insufficiency, this form
can present anytime from childhood until adulthood. It is distinguished from the infantile-onset form by the absence of
severe cardiac involvement. While life expectancy can vary, death generally occurs due to respiratory failure.
The image on the left depicts a normal muscle cell, while the image on the right illustrates what may happen in
Pompe disease. As glycogen accumulates in affected cells, it may cause the lysosomes to enlarge, eventually impairing muscle function.
Dutch pathologist J.C. Pompe first described a 7-month-old infant who died suddenly from the disease in 1932.
After observing idiopathic hypertrophy of the heart and the accumulation of glycogen in all types of tissues, he labeled the disorder
"cardiomegalia glycogenica diffusa." Two other reports of infants with similar manifestations soon followed, calling the disorder Pompe
disease. Nobel laureate G.T. Cori, who discovered the course of catalytic metabolism of glycogen, classified the disorder as glycogen
storage disease type II (GSD-II) in 1954 to reflect the impaired glycogen metabolism of affected patients.
The nomenclature for Pompe disease has varied over the years, with synonyms that include acid maltase deficiency
(AMD), glycogenosis type II, glycogen storage disease type II (GSD-II), and GAA deficiency.
Based on Cori's research and the discovery of a new organelle, the lysosome, Hers and colleagues in 1963
deduced the metabolic basis of Pompe disease by linking the deposition of glycogen to an inherited absence or shortage of lysosomal
enzymes. As a result, Pompe disease was the first to be classified as a lysosomal storage disease (LSD). This breakthrough led to
the ability to diagnose the disease and enabled the search for the chromosomal location of the genetic mutation. In 1970, Engel
published one of the early reports of a late-onset form of the disease, describing four adults with syndromes mimicking that of
muscular dystrophy or other myopathies. Nine years later, the gene responsible for the disorder was localized to chromosome 17
and designated GAA on the human gene map.
Pompe is a rare disease. Current estimates put the overall disease incidence at 1 in 40,000 live births.
Worldwide prevalence may be somewhere between 5,000 and 10,000.
Given the wide range of clinical presentations for Pompe disease, and the rarity of the disorder,
the clinical paths to diagnosis tend to vary tremendously. Infants may present with muscle weakness, feeding difficulty,
and/or cardiomegaly while older patients may initially complain of muscle weakness or respiratory distress.
The physical findings in adults may be particularly non-specific and/or suggest more common myopathic
disorders. Differential diagnosis is especially difficult due to the wide range of symptoms commonly observed in other diseases
and because many Pompe disease symptoms are highly variable across patients. As a result, the diagnosis of Pompe disease may
first require the elimination of other possible causes.
While diagnosis is challenging, there are various methods to aid in narrowing down the diagnostic
investigation from the clinical manifestations observed. Diagnostic workups, such as electromyography (EMG) or electrocardiography
(ECG), may help further reveal the functional manifestation. More targeted tests, such as enzyme level testing, may aid in
definitive diagnosis of Pompe disease.
Regardless of what steps precede it, a conclusive diagnosis generally requires that a biopsy of cultured
skin fibroblasts or muscle tissue demonstrate reduced or absent activity for the lysosomal enzyme acid alpha-glucosidase (GAA).
For those who learn they are at risk of being a Pompe disease carrier during pregnancy,
prenatal screening can determine whether
an unborn child will be affected by the disease.
At present, no standardized diagnostic protocol has been universally adopted for Pompe disease.
Consultation with specialists such as geneticists, neurologists, or endocrinologists who may be more familiar with the
disease and who use qualified laboratories may help to expedite the diagnosis.
Testing in Pompe disease
Enzyme Activity Testing of Cultured Skin Fibroblasts or Muscle Tissue
Enzyme activity testing via a cultured skin fibroblast or muscle biopsy is the definitive step in the diagnostic process, as it can provide proof of
low or absent acid alpha-glucosidase (GAA) activity and render a conclusive diagnosis of Pompe disease. Using cultured skin fibroblasts may be preferable
to a muscle biopsy due to the less invasive approach. Cultured skin fibroblasts may also be more conclusive in testing for Pompe disease. A muscle biopsy
can provide histopathological information about the level of glycogen storage within the lysosomes of muscle cells and may also return faster results.
Enzyme activity testing shows that the GAA deficiency is more pronounced in infantile-onset patients than in late-onset patients.
In some infants, the test reveals a complete absence of enzyme activity while in late-onset patients, the severity of the deficiency can vary dramatically.
Researchers report that most infants generally demonstrate less than 1% of normal GAA enzyme activity, while juveniles display less than 10% and adults
less than 40%, as measured in skin fibroblasts.
Histopathologic examination of muscle biopsies--which is not necessary for a diagnosis but may offer other
helpful findings--can reveal the degree of glycogen deposition within the lysosomes of muscle cells. Vacuoles generally stain positive for glycogen
and, in some cases, for the lysosomal enzyme acid phosphatase as well. The increase of acid phosphatase, which catalyzes the conversion of orthophosphoric
monoester and water into alcohol and orthophosphate, may be due to a compensatory effort. In infantile-onset patients, the increase in glycogen content
can be more than tenfold, while the elevation in late-onset patients generally ranges from normal to threefold.
Enzyme Levels (CK, AST, ALT)
A 1999 study found that creatine kinase (CK) elevation is a
sensitive marker for Pompe disease. Of 18 patients examined, 18 (100%) demonstrated elevated CK levels, while a review of the literature revealed
that 94.3% of patients displayed increased levels. The greatest elevation can be found in infantile-onset patients (as high as 2000 IU/L),
while in some cases, adults may have CK levels within the normal reference range. A blood test including a CK examination may be ordered as an
early step to determine whether more invasive testing is warranted.
Patients may demonstrate elevated levels of aspartate aminotransferase
(AST) and alanine aminotransferase (ALT). There
has been at least one report in which these laboratory findings served as the first clue in a juvenile patient. DiFiore and colleagues in 1993
described a case in which a still asymptomatic juvenile patient presented only with an isolated rise in AST.
Note that Pompe patients typically do not display any abnormalities of glucose metabolism such as hypoglycemia. In
addition, Pompe patients usually have normal responses to epinephrine and glucagon administration.
In some cases, a neurology
consult is requested in the early stages of diagnosis as a result of clinical suspicion of a neuromuscular disorder. An EMG exam generally
reveals a myopathic pattern in all Pompe patients, although some muscles may appear normal in late-onset patients. Other common findings
may include pseudomyotonic discharges (myotonic discharges without clinical myotonia), fibrillation potentials, positive sharp waves, and
excess electrical irritability. In addition, there are usually no abnormalities in conduction times for motor and sensory nerves.
In other instances, a chest X-ray showing the presence of
cardiomegaly starts the investigation while in other cases another laboratory test provides the first clue.
Echocardiography [ECG] and Electrocardiography (ECHO)
cardiology consult is generally warranted in infantile-onset patients. Depending on the patient's individualized presentation, this may occur
before or after clinical suspicion of a myopathic disorder is aroused.
Both echocardiography and electrocardiography can determine the degree of cardiac involvement. In infants, these
imaging studies play a key role in establishing whether the patient has infantile-onset or late-onset Pompe disease. Infantile-onset patients
generally show massive cardiomegaly while late-onset patients rarely ever display hypertrophy of the heart.
Certain findings are common in Pompe disease. Echocardiography may reveal left ventricular (LV) thickening
and/or outflow obstruction in infantile-onset patients, while the ECG exam typically shows a shortening of the PR interval as well as
very tall and broad QRS complexes. Late-onset patients usually have normal patterns.
CLINICAL SIGNS & SYMPTOMS
The clinical manifestations of Pompe disease may present individually or as a suspicious cluster of symptoms,
depending on the patient. The following are among the most common signs and symptoms recorded in the literature for the two phenotypes.
In the infantile-onset form, the signs and symptoms tend to present swiftly while in the late-onset form, the disease is more slowly progressive.
Cognitive function is generally normal in patients with Pompe disease.
Progressive muscle weakness
Macroglossia (and in some cases, protrusion of the tongue)
Cardiomegaly (massive) and/or cardiac failure
Failure to meet developmental motor milestones
Difficulty swallowing, sucking, and/or feeding
Laxity of facial muscles
- Progressive proximal muscle weakness, especially in the trunk
- Progressive muscle weakness in the lower limbs
- Respiratory insufficiency
- Exercise intolerance
- Exertional dyspnea
- Sleep apnea
- Morning headaches
- Lordosis and/or scoliosis
- Macroglossia (uncommon)
- Difficulty chewing or swallowing
- Increased frequency of respiratory infections
- Decreased deep tendon reflexes
- Gower sign
- Lower back pain
- Failure to meet motor milestones (children)
Historically, Pompe disease has sometimes been misdiagnosed as limb girdle muscular dystrophy, Duchenne muscular
dystrophy, or polymyositis. Depending on the individual's presenting symptoms and age of onset, there may be several other possible causes
to evaluate during the diagnostic query. The table below summarizes the more common differential diagnoses as well as the shared manifestations
that may be suggestive of that particular disease.
Acute Werdnig-Hoffman disease (Spinal muscular atrophy I)
- Hypotonia, progressive proximal muscle weakness, absent reflexes
Glycogen storage diseases III, VI
- Breathlessness, feeding difficulties, cardiomegaly, heart failure
Idiopathic hypertrophic cardiomyopathy
- Hypotonia, cardiomegaly, muscle weakness, elevated creatine kinase (CK)
- Inflammation of the myocardium contributing to cardiac enlargement
- Duchenne muscular dystrophy (DMD)
- Progressive proximal muscle weakness, respiratory impairment, difficulty walking
- Glycogen storage diseases III, VI
- Glycogen storage disease V
- Elevated creatine kinase (CK), muscle cramps during exercise
- Liver failure
- Limb girdle muscular dystrophy (LGMD)
- Progressive muscle weakness in the pelvis, legs, or shoulders
- Unexplained muscle weakness
- Rigid spine syndrome
- Spinal rigidity, lower back pain
- Rheumatoid arthritis
- Scapuloperoneal syndromes
- Progressive muscle weakness behind the knees and around the shoulder blades
- Sleep apnea
- Morning headaches, frequent nocturnal awakenings, daytime fatigue and drowsiness
Prenatal diagnosis is available for Pompe disease in cases where it may
be warranted, such as subsequent pregnancies in families with an affected child or when a parent
presents with the late-onset form. In fact, Pompe disease was one of the first genetic disorders for
which researchers attempted diagnosis prior to birth using amniocentesis, with the first published
reports appearing in the late 1960s. Today, prenatal diagnosis can be made with either amniocentesis
or, more commonly, direct enzyme analysis of uncultured chorionic villi cells, primarily using
4-methylumbelliferyl-a-D-glucoside (4MUG) as substrate. 4MUG is a substance upon which the acid
alpha-glucosidase (GAA) enzyme acts
The direct enzyme analysis of uncultured chorionic villi cells offers additional benefits
as it allows for early diagnosis (12th week of pregnancy) and potentially as quick as a one day turnaround for
results. In some cases, DNA analysis may also be used as a supportive method to confirm a prenatal diagnosis
of Pompe disease when the particular defect involved is known. In addition, it can enable definitive carrier
detection in the patient's family.
A recent study has explored the use of plasma and dried blood spots to test for Pompe
disease in newborns. It remains to be seen how reliable or accepted this diagnostic technique will be in common
In the absence of an approved treatment for Pompe disease, supportive therapy is used to manage
symptoms and minimize complications whenever possible. While these multidisciplinary approaches cannot generally alter
the disease course, they may impact quality of life. Physicians play an important role in coordinating the care for Pompe
patients and should be consulted whenever adjunctive care is implemented.
As a result of the severe weakening of the diaphragm and other respiratory muscles,
respiratory therapy may become a critical component of disease management. Many individuals with Pompe disease eventually
require mechanical ventilation to reduce or eliminate the work of breathing. Other techniques involve the use of an
incentive spirometer and intermittent positive pressure breathing (IPPB) to expand the lungs. Patients requiring 24-hour
ventilatory support for prolonged periods may be considered for a tracheostomy.
Dietary therapy is sometimes attempted in Pompe disease as case studies have shown that some patients
will demonstrate clinical improvement in conjunction with a high-protein, low-carbohydrate diet or, alternatively, a diet rich in
amino acids. In addition, patients who are extremely weak--especially infants--may require tube feeding in order to maintain proper
nutrition and prevent aspiration.
Patients who begin to lose mobility due to weakened muscles may also benefit from physical therapy.
A customized exercise and/or physical therapy program may help to preserve range of motion and strength, while the use of assistive
devices such as orthotics, canes, or walkers may help with ambulation. In advanced cases, a wheelchair may be indicated.
To devise a full spectrum of supportive therapy, consultation with a respiratory therapist, physical therapist, occupational
therapist, speech therapist, and/or registered dietician may be warranted.
One of the most crucial avenues of support is respiratory therapy, including the use of mechanical
ventilation to aid patients with weakened diaphragms and other respiratory muscles. The use of mechanical ventilation can
also prolong survival in late-stage cases, as patients with acute respiratory failure may be able to live for more than a
decade longer with proper ventilatory support.
Ideally, patients should be referred to a pulmonologist prior to the onset of respiratory failure,
although in many cases the signals may be subtle. Patients with exercise intolerance may not complain of dyspnea given their
inability to exert themselves, so other symptoms may present first. Morning headaches and somnolence are two early manifestations
that may warrant further investigation. Other signs include a decrease in vital capacity in a supine position and orthopnea. To
determine the cause, a sleep evaluation or gas exchange assessment may be indicated.
In many cases, a ventilatory support may only be needed initially at night to address nocturnal
carbon dioxide retention and sleep disordered breathing (SDB). Because diurnal hypoventilation usually follows nocturnal
hypoventilation, patients may increasingly need ventilation during the day as well.
Patients with growing respiratory impairment typically begin by using non-invasive ventilation devices
that deliver air through a mask that fits over the nose or mouth, or both. These devices provide the advantages of convenience,
portability, and low complications. Compared to invasive devices, they are associated with lower cost and morbidity, fewer infections,
and reduced caregiver burden.
Currently, there are several different modes of ventilation available depending on patients' needs and ability
to breathe spontaneously. Patients with the strength to inhale on their own may prefer a ventilator that follows their own breathing
pattern, while others may need a ventilator programmed to automatically deliver breaths in preset cycles. To initiate use, patients
are generally referred to a respiratory therapist (RT), who may be available in a hospital or clinic setting. In some cases, the RT
may visit patients' homes to provide training and assistance. The RT then typically follows up with patients for several weeks to
ensure that the mask fits properly (with no leaks) and adjust the ventilator settings.
Non-invasive ventilation may not be feasible for small children, patients with claustrophobia, those with
excessive secretions, patients with swallowing or coughing difficulty, or advanced cases requiring more intensive respiratory support.
In other cases, patients may not begin mechanical ventilation unless they are hospitalized for respiratory
failure, which in some cases occurs when infection potentiates respiratory impairment. Intubation is generally employed in this
scenario to deliver conditioned and oxygenated air to the lungs. Once respiratory function stabilizes, "weaning" is usually attempted
to determine if patients can breathe on their own entirely, or for a portion of the day. Some patients may not respond to weaning
and may become permanently dependent on ventilation, however.
Although definitive guidelines have not been established, patients who appear that they will require mechanical
ventilation 24-hours a day for a prolonged period of time and do not respond to weaning may become candidates for tracheostomy. Most
modern devices have mechanisms that facilitate speech, such as a one-way valve that can be used along with a deflated cuff to allow
patients to converse. Tracheostomy has been associated with improved patient comfort and enhanced ability to participate in
rehabilitation-oriented activities. Tracheostomy openings should be cleaned daily to prevent infection.
Another component of respiratory therapy is intermittent positive pressure breathing (IPPB), which can be
administered by a RT in the hospital, clinic, or home setting in 10-15 minute sessions. IPPB helps to increase the patient's depth
of breathing and can be used to deliver aerosol medications such as mucolytics to the lungs. In some cases, an incentive spirometer
may also be employed to increase inhaled lung volume and help eliminate mucus and saliva. Other "respiratory toilet" techniques that
may help to clear pulmonary secretions include frequent suctioning and cough assist measures such as chest percussion.
Preventing infections is an important part of the total care of Pompe patients. Given that most patients
have some degree of respiratory impairment, they are often highly susceptible to pulmonary exacerbations such as bronchitis and
pneumonia. Due to this vulnerability, vaccinations such as a flu shot, pneumoccal vaccine, or respiratory syncytial virus (RSV)
vaccine may be considered. Infants in particular may encounter aspiration pneumonia as a major complication. As a result, any
infection should be treated promptly before it progresses to a more serious stage. Should an infection worsen despite measures
to curb it, mechanical ventilation can support patients through this critical period and help to prevent a decline in clinical
Dietary therapy may be warranted in both
infantile-onset and late-onset patients who are chronically
underweight and struggle to take in enough calories on a daily
basis. A referral to a registered dietician (RD) may be
appropriate for determining the patient's optimal caloric
intake and recommendations as to how to achieve it. Those
with difficulty swallowing, a risk of aspiration, or who
require invasive ventilation for short periods of time may
be indicated for nasogastric (NG) or nasoenteric (NE) tube
feeding, while those who require indefinite tube feeding may
be candidates for permanent tube feed placement in the abdomen.
Tube feeding is generally more common in infantile-onset patients
as a result of their severe muscle weakness, ventilator dependency,
Long-term tube feed placement
may be achieved via a gastrostomy tube (G-tube),
jejunostomy tube (J-tube), or a gastrojejunostomy
tube (GJ-tube). The location of the catheter and the
placement technique--including percutaneous, endoscopic,
radiological, and surgical--varies depending on the patient,
physician, and facility. G-tubes deliver blenderized food to
the stomach while J-tubes and GJ-tubes bypass the stomach to
deliver liquid nutrients to the intestine. Tube feeding is
generally considered a more benign option than total parenteral
nutrition (TPN), or intravenous feeding. As a result, TPN
is typically reserved for patients in whom enteral feeding
is contradicted or inadequate.
There may be other reasons for dietary
therapy as well. Researchers have theorized that muscle wasting
and weakness in Pompe disease may result from increased muscle
protein breakdown, and accordingly, that efforts to restore the
net protein balance may prove ameliorative. Several early case
reports studying clinical improvement in late-onset patients
treated with high-protein diets have suggested the potential
to counteract muscle deterioration through diet.
In recent years, however, research has shown
that not all patients with Pompe disease will benefit from this
approach. A 1997 review of the literature (eight published reports
totaling 16 subjects) found that only 25% of patients treated with
a high-protein diet displayed improvement in either respiratory
or skeletal muscle function. Still, many physicians currently
prescribe a specialized high-protein, low-carbohydrate diet to
determine whether individual patients will respond.
A variation of the high-protein diet is
dietary supplementation with amino acids. A 1990 case report
suggested that supplementing the patient's general diet with
the branched chain amino acids (BCAA) including valine, isoleucine,
and leucine may have positive effects.
Another common supplement is alanine,
a crystalline amino acid involved in both protein and glucose
metabolism that is often depleted in Pompe disease. In 2002,
researchers published the case study of an infant who presented
with symptoms at 12 months of age and who was treated with
L-alanine oral supplementation. After five years, the
patient's cardiomyopathy had resolved almost completely
and skeletal myopathy progressed slowly. Although
dietary therapy is generally considered to have more
of a role in late-onset patients, this study posits
that supplementation with L-alanine may have value in infants.
Pompe patients may benefit from physical
therapy as well. For young children with muscle weakness,
physical therapy may help them learn how to move and interact
with their environment. It also helps to prevent contractures.
In addition, physical therapists can teach parents ways to
facilitate a young child's growth and development. As Pompe
disease progresses, physical therapy may help preserve range
of motion and strength, as well as minimizing discomfort from
musculo-skeletal changes. Chest PT is very important in patients
with infantile-onset Pompe disease.
Some physicians have prescribed exercise
programs that may help late-onset Pompe patients stay conditioned
and maintain their strength. Before patients begin to exercise,
however, it may be necessary to perform testing to determine
their exercise tolerance. Based on these results, a customized
exercise regimen can be developed to match the individual's
needs and capabilities. This regimen often includes submaximal aerobic exercise.
There are also specific
resistance exercises, such as inspiratory muscle
training, that may strengthen the diaphragm muscles.
In addition, occupational therapy may help late-onset
patients learn new ways to complete daily tasks and
job duties while speech therapy may be indicated as an early
intervention for patients who have speaking or eating difficulties.
Speech therapists can also work with patients who have tracheostomies
to enhance upper airway function.
Assistive devices may help patients
with weakened leg, pelvic, and trunk muscles to stay mobile.
Some may benefit from orthotics--while others may find that
canes, walkers, or wheelchairs may be needed for ambulation.
In addition, there are a number of other mobility and
household aids, such as shower chairs and mechanical
lifts, that may prove helpful to patients and their
families at advanced stages.
Since there is currently no treatment
to cure or slow the progression of Pompe disease, most patients receive
symptomatic treatment. Current investigations are primarily focused on
two approaches: enzyme replacement therapy (ERT) and
Bone marrow transplantation has also been explored.
Enzyme Replacement Therapy (ERT)
Enzyme replacement therapy (ERT)
is intended to directly address the underlying metabolic defect via intravenous infusions of recombinant human GAA (rhGAA) enzyme. Clinical trials are currently underway to determine the safety and effectiveness of enzyme replacement therapy in humans. For more information on clinical trials investigating ERT, please visit:
- Genzyme Clinical Trials
Gene therapy is in the
early stages of pre-clinical investigation and takes a genetic approach
to correcting Pompe disease. It aims to circumvent the inborn genetic
mutation at the root of Pompe disease by introducing a working copy of
the GAA gene into the tissues, in most cases via a modified virus. Gene
therapy has been studied using both ex vivo and in vivo
approaches. However, there are some serious safety concerns associated
with this approach in other diseases, and there are currently no approved
Bone Marrow Transplantation
Previous attempts at bone marrow transplantation for Pompe disease have not met with success. There is some data to suggest that next-generation techniques might be more effective, however. Further studies will likely be needed to determine whether bone marrow transplantation may be beneficial. Until that time, it appears to be less effective than the other approaches under investigation.